Alternative titles; symbols
SNOMEDCT: 784381008; ORPHA: 357058, 357074; DO: 0070134;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.31 | Cutis laxa, autosomal recessive, type IIA | 219200 | Autosomal recessive | 3 | ATP6V0A2 | 611716 |
A number sign (#) is used with this entry because autosomal recessive cutis laxa type IIA (ARCL2A) is caused by homozygous or compound heterozygous mutations in the ATP6V0A2 gene (611716), which encodes the alpha-2 subunit of the V-type H+ ATPase, on chromosome 12q24. The occurrence of mutations in the same gene in wrinkly skin syndrome (WSS; 278250) indicates that autosomal recessive cutis laxa type IIA and some cases of WSS represent variable manifestations of the same genetic defect.
Autosomal recessive cutis laxa type II represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type II), and ARCL2B, those without a metabolic disorder (summary by Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Genetic Heterogeneity of Cutis Laxa Type II
ARCL2A is caused by mutation in the ATP6V0A2 gene. ARCL2B (612940) is caused by mutation in the PYCR1 gene (179035). ARCL2C (617402) is caused by mutation in the ATP6V1E1 gene (108746). ARCL2D (617403) is caused by mutation in the ATP6V1A gene (607027). ARCL2E (619451) is caused by mutation in the LTBP1 gene (150390).
Fittke (1942) described a 10.5-month-old female whose skin from birth had been in loose, redundant folds. The face was spared, however. On stretching, the skin returned only slowly to its original position. The skeletal system showed widely persistent fontanels, slight oxycephaly, and dislocation of one hip. The parents were not known to be related but lived in an area of Europe where most persons were related in some degree. The mother, aged 25 years, had long suffered from 'weak knee joints.' An 8-year-old cousin of the proband showed the same skin changes, as well as pigeon breast, static scoliosis, and flat feet. The fontanels had not closed until the third year. The case of Debre et al. (1937) may be identical. Theopold and Wildhack (1951) restudied Fittke's family and demonstrated consanguinity of the parents of the affected cousin.
Reisner et al. (1971) described 2 sisters with congenital cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. The parents were first cousins. The authors suggested that the severe form may occur only or mainly in females because it is lethal to the male fetus. They also suggested that this disorder is unusually frequent in Saudi Arabia. Sakati et al. (1983) reported 6 cases, bringing the reported total to 13, all female, and raised the question of X-linked dominant lethal in the hemizygous male. However, Philip (1978) observed a case in a male infant. Fitzsimmons et al. (1985) and Goldblatt et al. (1988) also reported males with this special cutis laxa syndrome. Allanson et al. (1986) reported an affected girl with first-cousin parents of Saudi Arabian extraction.
Ogur et al. (1990) reported the cases of Turkish brother and sister. Van Maldergem et al. (1989) pictured a 23-month-old patient born to Turkish first-cousin parents. Facial features included a bossing of the forehead, reversed-V eyebrows, and downward slant of palpebral fissures. The patient also had enormous bilateral inguinal hernias. Imaizumi et al. (1994) described a nineteenth case; the ratio of males to females was 5 to 14. Their patient, a 5-year-old boy, had pre- and postnatal growth retardation, delayed motor development, cutis laxa, delayed closure of large fontanels, congenital hip dislocation, and characteristic facies.
Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, Morava et al. (2005) performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome. They described 5 patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay, and neurologic findings. Three of these 5 children had an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans, and 2 of these patients had bilateral pachygyria on brain MRI. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were identified in the FBLN5 gene (604580). Morava et al. (2005) concluded that these patients had a unique combined glycosylation defect with a distinct clinical phenotype and that a combined defect of glycosylation may be a causative factor in autosomal recessive congenital cutis laxa.
Morava et al. (2008) described 10 patients with cutis laxa and congenital disorder of glycosylation, including 3 patients reported by Morava et al. (2005). Clinical features included transient feeding problems in infancy, late closure of the fontanelles, and variable central nervous system involvement including hypotonia, developmental delay, mental retardation, seizures, microcephaly, pachygyria, and myopia. All patients had dysmorphic facial features with downslanting palpebral fissures, midface hypoplasia, anteverted nares, short nose and small mouth. Other features included congenital hip dislocation and joint hyperlaxity. Skin biopsy showed decreased amounts of elastin and abnormal elastin structure. Biochemical analysis showed a combined defect of N- and O-glycosylation. All patients had mutations in the ATP6V0A2 gene (Kornak et al., 2008).
Van Maldergem et al. (2008) reported 11 patients from 9 families with the Debre type of cutis laxa, which was confirmed by genetic analysis of the ATP6V0A2 in all patients except 1. All had dysmorphic craniofacial features, most commonly including large anterior fontanel, prominent supraorbital ridges and nasal root, downslanting palpebral fissures, and coarse hair. Four patients had microcephaly. The skin showed generalized overfolding and wrinkling, but no hyperelasticity, and skin biopsies showed a sparse elastin network. Connective tissue problems were common, and included inguinal hernia, hip dislocation, and high myopia. There tended to be improvement of cutis laxa throughout childhood. All had mental retardation that varied in severity, and 5 patients developed refractory seizures. Transferrin isoelectric focusing showed CDG type II. Brain imaging was performed in 9 patients, 8 of whom showed a cobblestone-like malformation predominantly in the posterior frontal, perisylvian, and parietal regions. It resembled polymicrogyria, but the cortical ribbon appeared smooth in some areas and irregular in others. These cortical malformations were reminiscent of those observed in the alpha-dystroglycanopathies, such as Walker-Warburg syndrome (see, e.g., MDDGA1, 236670). Two patients had a Dandy-Walker malformation.
Morava et al. (2009) reviewed the spectrum of clinical features of the various autosomal recessive syndromes associated with cutis laxa, including ARCL1 (219100), ARCL2, de Barsy syndrome (219150), X-linked cutis laxa (304150), WSS, geroderma osteodysplasticum (GO; 231070), and Costello syndrome (218040).
Relationship to Wrinkly Skin Syndrome
Zlotogora (1999) pointed out that the 2 sisters reported by Reisner et al. (1971) as one of the first examples of the syndrome of cutis laxa with growth and developmental delay were reported later, along with their newborn brother, as examples of WSS. Conformation that these 2 syndromes represent variable presentations of one disorder may be provided by the report of Ogur et al. (1990) on 2 affected Turkish sibs. The boy was severely affected with the classic form of cutis laxa and developmental delay, while his sister showed improvement with the years and at the age of 6.5 years presented with a relatively mild disease, including cutaneous manifestations similar to those found in the wrinkly skin syndrome. Another source of confusion is that some of the children reported with recessive infantile cutis laxa with growth and developmental delay were, in fact, affected with Costello syndrome (see later). Since the wrinkly skin syndrome is not a true form of cutis laxa (Azuri et al., 1999), Zlotogora (1999) suggested use of the designation 'wrinkly skin syndrome' for all of the patients who were reported as affected with either one or the other of these 2 syndromes.
Congenital disorders of glycosylation (CDG) form a growing class of hereditary disorders caused by defective glycosylation at the level of the endoplasmic reticulum or the Golgi apparatus (Freeze, 2006). An association of a cutis laxa phenotype with CDG has been described (Morava et al., 2005), and wrinkly skin has been observed in an individual with a defect in the conserved oligomeric Golgi (COG) complex (Wu et al., 2004). On the basis of these observations, Kornak et al. (2008) investigated glycosylation of serum proteins isolated from individuals with autosomal recessive cutis laxa type II and found that they showed a CDG type II pattern, which corresponds to a defect of N-glycosylation at the level of processing in the Golgi apparatus. Reduced sialic acid content of the glycans from affected individuals indicated that sialylation, a terminal step of glycan synthesis, was particularly impaired. A strict correlation between phenotype and degree of glycan abnormality was not seen.
In 15 consanguineous families with a cutis laxa or wrinkly skin syndrome phenotype, Kornak et al. (2008) performed homozygosity mapping, microsatellite marker analysis, and haplotype analysis and identified a 5.7-Mb region of homozygosity on chromosome 12q24 between markers D12S395 and D12S304 containing the ATP6V0A2 gene.
In 12 families with diagnoses of either autosomal recessive cutis laxa type II or wrinkly skin syndrome, Kornak et al. (2008) identified 10 different loss-of-function mutations in the ATP6V0A2 gene. The mutations resulted in abnormal glycosylation of serum proteins (CDG II) and caused an impairment of Golgi trafficking in fibroblasts from affected individuals. The results indicated that the alpha-2 subunit of the proton pump has an important role in the Golgi function.
Leao-Teles et al. (2010) stated that 1 of the patients studied by Kornak et al. (2008) and found to have a mutation in the ATP6V0A2 gene (patient 'CoFe') displayed the full clinical picture of the De Barsy syndrome (see 219150), including cutis laxa, facial dysmorphism, dwarfism, psychomotor retardation, dystonia, congenital hip dysplasia, and corneal dystrophy requiring repeated corneal transplantation. Leao-Teles et al. (2010) suggested that a subgroup of patients with de Barsy syndrome belongs to the spectrum of ATP6V0A2-associated CDG, and recommended that mutations in the ATP6V0A2 gene be sought in patients diagnosed with de Barsy syndrome. Morava et al. (2010) noted that none of their cohort of 6 patients with de Barsy syndrome had N-linked or O-linked glycosylation abnormalities nor mutations in ATP6V0A2; they stated that further description and photographs of patient CoFe would be helpful, since corneal abnormalities with a movement disorder would widen the range of symptoms evoking glycosylation studies in patients with cutis laxa.
In 13 patients with ARCL2, Fischer et al. (2012) identified 17 ATP6V0A2 mutations: 1 mutation of the start codon, 3 missense mutations, 3 nonsense mutations, 3 splice site mutations, 3 in-frame deletions, and 4 frameshift mutations; 14 of the mutations were novel. All mutations but 1 were found in homozygous or compound heterozygous state. A heterozygous mutation was detected at the genomic as well as the cDNA level in a 40-year-old patient (patient 2), but a pronounced nonsense-mediated decay of the ATP6V0A2 mRNA in fibroblasts corroborated an ATP6V0A2-related ARCL2. Fischer et al. (2012) suggested that the second mutation most probably resided in noncoding regions not included in the mutation screening. This patient, who was described as the oldest affected individual reported to that time, showed a strikingly progressive phenotype leading to kyphoscoliosis, facial coarsening, mild to moderate mental retardation, and seizures without progression.
Exclusion Studies
In 3 unrelated patients with autosomal recessive cutis laxa type II, Scherrer et al. (2008) excluded mutations in the FBLN4 (604633), FBLN5 (604580), and LOX (153455) genes. The ATP6V0A2 gene was not studied in these patients.
Under the title 'congenital cutis laxa with retardation of growth and development,' Patton et al. (1987) reported 7 patients. Autosomal recessive inheritance was supported by the inclusion of 2 brother-sister pairs. In 1 of these, the parents were second cousins from the Middle East. The authors were impressed with the occurrence of widespread dental caries. Later, Patton and Baraitser (1993) reviewed 5 of the cases and concluded that the appropriate diagnosis was Costello syndrome (218040). Davies and Hughes (1994) reviewed case 7 from the paper and, on both history and clinical examination, made 'an unequivocal diagnosis of Costello syndrome.'
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